Cadmium (Cd2+) is an important industrial and environmental pollutant that can cause severe damage to a variety of organs including the lung, kidney, liver, and bone. In addition, Cd2+ has been shown to have teratogenic and carcinogenic activities. In spite of its importance as an environmental health problem, relatively little is known about the specific cellular and molecular mechanisms by which Cd2+ produces its adverse effects. The long-term objective of this project is to identify some of these mechanisms. Evidence from the literature suggests that some of the effects of Cd2+ in vivo may result from the disruption of the junctions between cells in various epithelial and endothelial surfaces. Results of recent studies have shown that Cd2+ can selectively disrupt the Ca2+-dependent junctions between various types of epithelial cells in culture, and that these effects most likely result from the interaction of Cd2+ with the Ca2+-dependent cell adhesion molecule, E-cadherin. More studies that are recent have shown that Cd2+ can disrupt E-cadherin- and VE-cadherin-dependent cell-cell junctions in the lung and alter the localization of E-cadherin and N-cadherin in the kidney. Additional results on cells in culture suggest that the loss of cadherin-mediated adhesion results in the translocation of the cadherin-binding protein beta-catenin from the junctional complexes to the cell nucleus and possible alterations in gene expression. These results suggest that the cadherin/beta-catenin complex may be an important early target of Cd2+ toxicity in epithelial cells of the lung and kidney. The work described in this proposal is a direct extension of these previous studies, and is aimed at resolving two major issues. The first objective is to continue ongoing studies examining the effects of Cd2+ on the cadherin/catenin complex in vivo, and to determine if this mechanism might contribute to the toxic effects of Cd2+ in specific target organs such as the lung and the kidney, which are important targets of Cd2+ toxicity in humans. The second objective is to examine the possibility that the Cd2+-induced disruption of the cadherin/beta-catenin complex may lead to the translocation of beta-catenin from the junctional complexes to the nucleus and alterations in beta-catenin-regulated gene expression. These issues will be addressed by employing a multidisciplinary approach that includes both in vitro and in vivo studies that utilize a variety of physiologic, morphologic and biochemical techniques. Results of these studies should provide important new insights into the mechanisms by which Cd2+ produces some of its toxic effects. Furthermore, the results of these studies could have more general implications regarding the mechanisms by which toxic substances affect living organisms.